Anti-Tau antibodies and methods of use thereof

Abstract

In one aspect, antibodies that specifically bind to a human Tau protein are provided. In some embodiments, an anti-Tau antibody recognizes an epitope within residues 111-125 of full-length human Tau, an epitope within residues 251-270 and/or residues 346-360 of full-length human Tau, or an epitope within residues 186-205 of full-length human Tau. In some embodiments, an anti-Tau antibody specifically binds to phosphorylated human Tau, unphosphorylated human Tau, and/or multiple splice isoforms of human Tau. An anti-Tau antibody disclosed herein may also include one or two modified Fc polypeptides.

What is claimed is: 
     
       1. An isolated antibody or antigen-binding portion thereof that specifically binds to a human Tau protein, comprising the following complementarity determining regions (CDRs):
 (a) a heavy chain CDR1 having the amino acid sequence of any one of SEQ ID NOS:22, 150-154, 420-437, 586, and 587; 
 (b) a heavy chain CDR2 having the amino acid sequence of any one of SEQ ID NOS:23, 438-443, and 588; 
 (c) a heavy chain CDR3 having the amino acid sequence of any one of SEQ ID NOS:24 and 155; 
 (d) a light chain CDR1 having the amino acid sequence of any one of SEQ ID NOS:26, 156-158, and 444-459; 
 (e) a light chain CDR2 having the amino acid sequence of SEQ ID NO:27; and 
 (f) a light chain CDR3 having the amino acid sequence of any one of SEQ ID NOS:28, 159-162, and 460-462. 
 
     
     
       2. The isolated antibody of  claim 1 , comprising:
 (a) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:586, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:439, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:450, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461; or 
 (b) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:22, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:450, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461; or 
 (c) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:22, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:459, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461; or 
 (d) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:151, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:26, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (e) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:151, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:156, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (f) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:151, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (g) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:22, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (h) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:150, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:153, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (j) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:154, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (k) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:22, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:155, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (l) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:150, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:155, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (m) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:151, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:155, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (n) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:153, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:155, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (o) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:154, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:155, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (p) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:22, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:26, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28. 
 
     
     
       3. The isolated antibody of  claim 1 , comprising:
 (a) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:21 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:25; or 
 (b) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:145 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:149; or 
 (c) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:146 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:149; or 
 (d) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:147 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:149; or 
 (e) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:148 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:149; or 
 (f) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:146 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:463; or 
 (g) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:146 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:464. 
 
     
     
       4. The isolated antibody of  claim 1 , comprising:
 (a) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:586, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (b) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:586, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461; or 
 (c) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:586, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:450, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461; or 
 (d) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:587, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588 a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28; or 
 (e) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:587, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:158, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461; or 
 (f) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:587, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:450, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461. 
 
     
     
       5. The isolated antibody of  claim 4 , comprising:
 (a) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:602 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:604; or 
 (b) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:602 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:616; or 
 (c) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:602 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:463; or 
 (d) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:603 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:604; or 
 (e) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:603 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:616; or 
 (f) a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:603 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:463. 
 
     
     
       6. The isolated antibody of  claim 1 , wherein the antibody comprises:
 (a) a first antigen-binding portion comprising a first variable region that specifically binds to the human Tau protein, wherein the first antigen-binding portion comprises (i) a first heavy chain comprising a first Fc polypeptide and (ii) a first light chain; and 
 (b) a second antigen-binding portion comprising a second variable region that specifically binds to the human Tau protein, wherein the second antigen-binding portion comprises (i) a second heavy chain comprising a second Fc polypeptide and (ii) a second light chain, wherein the first Fc polypeptide and the second Fc polypeptide form an Fc dimer. 
 
     
     
       7. The isolated antibody of  claim 1 , wherein the antibody or antigen-binding portion thereof specifically binds to the human Tau protein with a binding affinity of less than about 50 nM. 
     
     
       8. The isolated antibody of  claim 1 , wherein:
 (a) the antibody or antigen-binding portion thereof specifically binds to a phosphorylated human Tau protein and/or an unphosphorylated human Tau protein; and/or 
 (b) the antibody or antigen-binding portion thereof specifically binds to two or more isoforms of the human Tau protein selected from the group consisting of 2N4R, 2N3R, 1N4R, 1N3R, 0N4R, and 0N3R; and/or 
 (c) the antibody or antigen-binding portion thereof exhibits cross-reactivity with a cynomolgus monkey Tau protein and/or a mouse Tau protein. 
 
     
     
       9. The isolated antibody of  claim 1 , wherein:
 (a) the antibody is a monoclonal antibody; and/or 
 (b) the antibody is a chimeric antibody; and/or 
 (c) the antibody is a humanized antibody. 
 
     
     
       10. The isolated antibody of  claim 1 , wherein the antigen-binding portion is a Fab, a F(ab′)2, a scFv, or a bivalent scFv. 
     
     
       11. An isolated polynucleotide comprising a nucleotide sequence encoding the isolated antibody of  claim 1 . 
     
     
       12. A method of reducing pathological Tau seeding and/or spreading in the brain of a subject and/or for treating a tauopathy in a subject, the method comprising administering to the subject the isolated antibody of  claim 1 . 
     
     
       13. The method of  claim 12 , wherein the tauopathy is a neurodegenerative tauopathy. 
     
     
       14. The method of  claim 13 , wherein the neurodegenerative tauopathy is selected from the group consisting of Alzheimer's disease, primary age-related tauopathy, progressive supranuclear palsy (PSP), frontotemporal dementia, frontotemporal dementia with parkinsonism linked to chromosome 17, argyrophilic grain dementia, amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam, corticobasal degeneration, chronic traumatic encephalopathy, Creutzfeldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down's syndrome, familial British dementia, familial Danish dementia, Gerstmann-Straussler-Scheinker disease, globular glial tauopathy, Guadeloupean parkinsonism with dementia, Guadelopean PSP, Hallevorden-Spatz disease, inclusion-body myositis, multiple system atrophy, myotonic dystrophy, neurofibrillary tangle-predominant dementia, Niemann-Pick disease type C, pallido-ponto-nigral degeneration, Parkinson's disease, Pick's disease, postencephalitic parkinsonism, prion protein cerebral amyloid angiopathy, progressive subcortical gliosis, subacute sclerosing panencephalitis, Huntington's disease, and tangle only dementia. 
     
     
       15. An isolated antibody or antigen-binding portion thereof that specifically binds to a human Tau protein comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:22, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:23, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:26, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:28. 
     
     
       16. The isolated antibody of  claim 15 , comprising a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:21 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:25. 
     
     
       17. An isolated antibody or antigen-binding portion thereof that specifically binds to a human Tau protein comprising a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:586, a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:588, a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:24, a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:450, a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:27, and a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:461. 
     
     
       18. The isolated antibody of  claim 17 , comprising a heavy chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:602 and a light chain variable region comprising an amino acid sequence that has at least 90% sequence identity to SEQ ID NO:463. 
     
     
       19. The isolated antibody of  claim 16 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:25. 
     
     
       20. The isolated antibody of  claim 18 , comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:602 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 463. 
     
     
       21. A method of treating a tauopathy in a subject, the method comprising administering to the subject the isolated antibody of  claim 15 . 
     
     
       22. A method of treating Alzheimer's disease in a subject, the method comprising administering to the subject the isolated antibody of  claim 15 . 
     
     
       23. The method of  claim 22 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:21 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:25. 
     
     
       24. A method of treating a tauopathy in a subject, the method comprising administering to the subject the isolated antibody of  claim 17 . 
     
     
       25. A method of treating Alzheimer's disease in a subject, the method comprising administering to the subject the isolated antibody of  claim 17 . 
     
     
       26. The method of  claim 25 , wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:602 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:25.